| 1. |
- Li, Jing, et al.
(författare)
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An obligatory role for neurotensin in high-fat-diet-induced obesity
- 2016
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 533, s. 411-415
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Tidskriftsartikel (refereegranskat)abstract
- Obesity and its associated comorbidities (for example, diabetes mellitus and hepatic steatosis) contribute to approximately 2.5 million deaths annually and are among the most prevalent and challenging conditions confronting the medical profession. Neurotensin (NT; also known as NTS), a 13-amino-acid peptide predominantly localized in specialized enteroendocrine cells of the small intestine and released by fat ingestion, facilitates fatty acid translocation in rat intestine, and stimulates the growth of various cancers. The effects of NT are mediated through three known NT receptors (NTR1, 2 and 3; also known as NTSR1, 2, and NTSR3, respectively). Increased fasting plasma levels of pro-NT (a stable NT precursor fragment produced in equimolar amounts relative to NT) are associated with increased risk of diabetes, cardiovascular disease and mortality; however, a role for NT as a causative factor in these diseases is unknown. Here we show that NT-deficient mice demonstrate significantly reduced intestinal fat absorption and are protected from obesity, hepatic steatosis and insulin resistance associated with high fat consumption. We further demonstrate that NT attenuates the activation of AMP-activated protein kinase (AMPK) and stimulates fatty acid absorption in mice and in cultured intestinal cells, and that this occurs through a mechanism involving NTR1 and NTR3 (also known as sortilin). Consistent with the findings in mice, expression of NT in Drosophila midgut enteroendocrine cells results in increased lipid accumulation in the midgut, fat body, and oenocytes (specialized hepatocyte-like cells) and decreased AMPK activation. Remarkably, in humans, we show that both obese and insulin-resistant subjects have elevated plasma concentrations of pro-NT, and in longitudinal studies among non-obese subjects, high levels of pro-NT denote a doubling of the risk of developing obesity later in life. Our findings directly link NT with increased fat absorption and obesity and suggest that NT may provide a prognostic marker of future obesity and a potential target for prevention and treatment.
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| 2. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 3. |
- Hindy, George, et al.
(författare)
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Rare coding variants in 35 genes associate with circulating lipid levels—A multi-ancestry analysis of 170,000 exomes
- 2022
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 109:1, s. 81-96
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Tidskriftsartikel (refereegranskat)abstract
- Large-scale gene sequencing studies for complex traits have the potential to identify causal genes with therapeutic implications. We performed gene-based association testing of blood lipid levels with rare (minor allele frequency < 1%) predicted damaging coding variation by using sequence data from >170,000 individuals from multiple ancestries: 97,493 European, 30,025 South Asian, 16,507 African, 16,440 Hispanic/Latino, 10,420 East Asian, and 1,182 Samoan. We identified 35 genes associated with circulating lipid levels; some of these genes have not been previously associated with lipid levels when using rare coding variation from population-based samples. We prioritize 32 genes in array-based genome-wide association study (GWAS) loci based on aggregations of rare coding variants; three (EVI5, SH2B3, and PLIN1) had no prior association of rare coding variants with lipid levels. Most of our associated genes showed evidence of association among multiple ancestries. Finally, we observed an enrichment of gene-based associations for low-density lipoprotein cholesterol drug target genes and for genes closest to GWAS index single-nucleotide polymorphisms (SNPs). Our results demonstrate that gene-based associations can be beneficial for drug target development and provide evidence that the gene closest to the array-based GWAS index SNP is often the functional gene for blood lipid levels. © 2021 American Society of Human Genetics
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| 4. |
- Schulz, Christina Alexandra, et al.
(författare)
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Genetic Predisposition for Renal Dysfunction and Incidence of CKD in the Malmö Diet and Cancer Study
- 2019
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Ingår i: Kidney International Reports. - : Elsevier BV. - 2468-0249. ; 4:8, s. 1143-1151
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Tidskriftsartikel (refereegranskat)abstract
- Background: Genome-wide association studies (GWAS) have identified >50 single nucleotide polymorphisms (SNP) in association with estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD) but little is known about whether the combination of these SNPs may aid in prediction of future incidence of CKD in the population. Methods: We included 2301 participants with baseline eGFR ≥60 mL/min per 1.73 m2 from the Malmö Diet and Cancer Study–Cardiovascular Cohort. The eGFR was estimated during baseline (1991–1996) and after a mean follow-up of 16.6 years using the CKD–Epidemiology Collaboration 2009 creatinine equation. We combined 53 SNPs into a genetic risk score weighted by the effect size (wGRSCKD), and examined its association with incidence of CKD stage 3A (eGFR ≤60 mL/min per 1.73 m2). Results: At follow-up, 453 study participants were defined as having CKD stage 3A. We observed a strong association between wGRSCKD and eGFR at baseline (P = 6.5 × 10−8) and at the follow-up reexamination (P = 5.0 × 10−10). The odds ratio (OR) for incidence of CKD stage 3A was 1.25 per 1 SD increment in the wGRSCKD (95% confidence interval [CI]: 1.12–1.39) adjusting for potential confounders (sex, age, body mass index [BMI], baseline eGFR, fasting glucose, systolic blood pressure (SBP), antihypertensive treatment, smoking, follow-up time). Adding wGRSCKD on the top of traditional risk factors did not improve the C-statistics (P = 0.12), but the Net Reclassification-Improvement-Index was significantly improved (cNRI = 21.3%; 95% CI: 21.2–21.4; P < 0.0001). Conclusion: wGRSCKD was associated with a 25% increased incidence of CKD per 1 SD increment. Although the wGRSCKD did not improve the prediction model beyond clinical risk factors per se, the information of genetic predisposition may aid in reclassification of individuals into correct risk direction.
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| 5. |
- Bao, Xue, et al.
(författare)
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Proteomic Profiles of Body Mass Index and Waist-to-Hip Ratio and Their Role in Incidence of Diabetes
- 2022
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 107:7, s. 2982-2990
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Tidskriftsartikel (refereegranskat)abstract
- Context: It is unclear to what extent the plasma proteome of abdominal fat distribution differs from that of body mass index, and whether the differences have clinical implications. Objective: To evaluate the difference between the plasma proteomic profiles of body mass index (BMI) and waist-to-hip ratio (WHR), and then examine the identified BMI- or WHR-specific proteins in relation to incidence of diabetes. Methods: Data were obtained from the Malmö Diet and Cancer-Cardiovascular Cohort study in the general community. Participants (n = 4203) with no previous diabetes (aged 57.2 ± 6.0 years, 37.8% men) were included. Plasma proteins (n = 136) were measured by the Proseek proximity extension method. BMI- and WHR-specific proteins were identified at baseline using a 2-step iterative resampling approach to optimize internal replicability followed by β coefficient comparisons. The identified proteins were considered internally replicated and were then studied in relation to incident diabetes by Cox proportional hazards regression analysis. The main outcome measure was incident diabetes over a mean follow-up of 20.3 ± 5.9 years. Results: After excluding 21 overlapping proteins and proteins that did not show significantly different associations with BMI vs WHR, 10 internally replicated proteins were found to be specific to BMI, and 22 were found to be specific to WHR (false discovery rate-adjusted P < .05). Of the WHR-specific proteins, 18 remained associated with diabetes risk after multivariate adjustments, whereas none of the BMI-specific proteins showed associations with diabetes risk. Conclusion: Abdominal fat distribution was associated with some unique characteristics of the plasma proteome that potentially could be related to its additional risk of diabetes beyond general obesity.
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| 6. |
- Brunkwall, Louise, et al.
(författare)
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The Malmö Offspring Study (MOS) : design, methods and first results.
- 2021
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Ingår i: European Journal of Epidemiology. - : Springer Nature. - 0393-2990 .- 1573-7284. ; 36, s. 103-116
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Tidskriftsartikel (refereegranskat)abstract
- As cardio metabolic disease manifestations tend to cluster in families there is a need to better understand the underlying mechanisms in order to further develop preventive strategies. In fact, genetic markers used in genetic risk scores, important as they are, will not be able alone to explain these family clusters. Therefore, the search goes on for the so called missing heritability to better explain these associations. Shared lifestyle and social conditions in families, but also early life influences may be of importance. Gene-environmental interactions should be explored. In recent years interest has grown for the role of diet-microbiota associations, as microbiota patterns may be shared by family members. In the Malmö Offspring Study that started in 2013, we have so far been able to examine about 4700 subjects (18-71 years) representing children and grandchildren of index subjects from the first generation, examined in the Malmö Diet Cancer Study during 1991 to 1996. This will provide rich data and opportunities to analyse family traits of chronic disease across three generations. We will provide extensive genotyping and phenotyping including cardiovascular and respiratory function, as well as markers of glucose metabolism. In addition, also cognitive function will be assessed. A 4-day online dietary recall will be conducted and gut as well as oral microbiota analysed. The ambition is to provide one of the first large-scale European family studies with individual data across three generations, which could deepen our knowledge about the role of family traits for chronic disease and its underlying mechanisms.
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| 7. |
- Fawad, Ayesha, et al.
(författare)
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Magnitude of rise in proneurotensin is related to amount of triglyceride appearance in blood after standardized oral intake of both saturated and unsaturated fat
- 2020
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Ingår i: Lipids in Health and Disease. - : Springer Science and Business Media LLC. - 1476-511X. ; 19:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: In rodents, neurotensin contributes to high fat diet induced obesity by facilitation of intestinal fat absorption. The effect of oral lipid load on plasma proneurotensin and relationship with plasma triglycerides in humans is unknown. AIM: To investigate the acute effects of an oral lipid load on proneurotensin and plasma triglycerides and their interrelationships in healthy individuals. SETTING/ METHODS: Twenty-two healthy subjects were given 150 mL of full milk cream (54 g fat) and 59 mL of pure olive oil (54 g fat) in the fasted state at two different occasions separated by at least 1 week in random order. Venous blood was drawn at fasted before 0 h (h) and at 1 h, 2 h and 4 h after ingestion. Post-ingested values of proneurotensin and plasma triglycerides were compared with fasting levels and post ingestion Area Under the Curve (AUC) of proneurotensin was correlated with that of plasma triglycerides. RESULTS: An immediate rise of plasma proneurotensin and plasma triglycerides were observed after ingestion of cream with maximum increase at 2 h for proneurotensin [mean (95% confidence interval)] of 22 (12-31) pmol/L (P < 0.001) and at 3 h for triglycerides of 0.60 (0.43-0.78) mmol/L (P < 0.001). Similarly, plasma proneurotensin and plasma triglycerides increased after ingestion of olive oil with maximum increase of proneurotensin at 3 h of 62 (46-78) pmol/L (P < 0.001) and plasma triglycerides at 3 h of 0.32 (0.18-0.45) mmol/L (P < 0.001). The post lipid load AUC for proneurotensin correlated significantly with the AUC for plasma triglycerides both after cream (r = 0.49, P = 0.021) and olive oil (r = 0.55, P = 0.008), respectively. CONCLUSION: Proneurotensin increases after an oral lipid load of both cream and olive oil and the rise of post-ingestion plasma triglycerides is significantly related to the rise of post-ingestion proneurotensin.
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| 8. |
- Fawad, Ayesha, et al.
(författare)
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Plasma Proneurotensin and Prediction of Cause-Specific Mortality in a Middle-aged Cohort During Long-term Follow-up
- 2022
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Ingår i: The Journal of clinical endocrinology and metabolism. - : The Endocrine Society. - 1945-7197 .- 0021-972X. ; 107:3, s. 1204-1211
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Neurotensin is associated with cardiometabolic diseases but its role with mortality risk in humans is unknown.OBJECTIVE: This work aims to examine the prediction of proneurotensin (Pro-NT) with respect to total and cause-specific mortality in a middle-aged cohort.METHODS: In the population-based middle-aged cohort (n = 4632; mean age, 57 years) of the Malmö Diet and Cancer Study, Pro-NT was assessed and total as well as cause-specific mortality was studied. Main cause of death was based on the International Classification of Diseases.RESULTS: During a mean follow-up of 20 ± 3 years, 950 men and 956 women died. There was significantly increased mortality risk in individuals belonging to the highest quartile (Q) of Pro-NT (Q4, Pro-NT ≥ 149 pmol/L) compared with Qs 1 to 3 (Pro-NT < 149 pmol/L), hazard ratio (HR), 95% CI of 1.29 (1.17-1.42; P < .001). Data were adjusted for sex and age. No significant interaction was observed between Pro-NT and sex on mortality risk. Individuals within Q4 vs Qs 1 to 3 had an HR of 1.41 (95% CI, 1.18-1.68; P < .001) for death due to cardiovascular disease (n = 595/4632); 2.53 (95% CI, 1.37-4.67; P = .003), due to digestive tract disease (n = 42/4632), 1.62 (95% CI, 1.04-2.52; P = .032) due to mental and behavioral disease (n = 90/4632); and 1.91 (95% CI, 1.15-3.19; P = .013) due to unspecific causes (n = 64/4632). There was no significant relationship between Pro-NT and deaths due to cancer, infections, neurological, or other causes. Adjustment for cardiovascular risk factors only marginally changed these results.CONCLUSION: The relationship between Pro-NT and total mortality risk was mainly driven by cardiovascular mortality, but high Pro-NT also predicts death from digestive, mental, and behavioral disease and deaths attributed to unspecific causes.
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| 9. |
- Fawad, Ayesha, et al.
(författare)
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Proneurotensin Predicts Cardiovascular Disease in an Elderly Population
- 2018
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 103:5, s. 1940-1947
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Tidskriftsartikel (refereegranskat)abstract
- Context: The gut hormone neurotensin promotes fat absorption, diet-induced weight gain, and liver steatosis. Its stable precursor-hormone fragment "proneurotensin" predicts cardiometabolic disease in middle-aged populations, especially in women. Objective: To test if proneurotensin predicts cardiovascular disease (CVD) and diabetes development in an elderly population and whether there are gender differences in this respect. Design, Setting, and Participants: Fasting proneurotensin was measured in plasma from 4804 participants (mean age 69±6 years) of the Malmö Preventive Project and subjects were followed up for development of CVD and diabetes during 5.4 years. Main Outcome Measures: Multivariate adjusted Cox proportional hazard models CVD were used to relate the proneurotensin to the risk of incident CVD and diabetes in all subjects and in genderstratified analyses. Results: In total, there were 456 first CVD events and 222 incident cases of diabetes. The hazard ratio [HR (95% confidence interval)] for CVD per 1 standard deviation (SD) increment of proneurotensin was 1.10 (1.01 to 1.21); P = 0.037, and the above vs below median HR was 1.27 (1.06 to 1.54); P = 0.011, with similar effect sizes in both genders. There was no significant association between proneurotensin and incident diabetes in the entire population (P = 0.52) or among men (P = 0.52). However, in women proneurotensin predicted diabetes incidence with a per 1 SD increment HR of 1.28 (1.30 to 1.59); P = 0.025 and an above vs below median HR of 1.41 (1.10 to 1.80); P = 0.007. Conclusions: In the elderly population, proneurotensin independently predicts development of CVD in both genders, whereas it only predicts diabetes in women.
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| 10. |
- Gottsäter, Mikael, et al.
(författare)
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A genetic risk score for fasting plasma glucose is independently associatedwith arterial stiffness : A Mendelian randomization study
- 2018
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Ingår i: Journal of Hypertension. - 0263-6352. ; 36:4, s. 809-814
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Tidskriftsartikel (refereegranskat)abstract
- Background: Arterial stiffness is known to be associated with a number of clinical conditions including hypertension, diabetes and dyslipidemia, and may predict cardiovascular events and mortality. However, causal links are hard to establish. Results from genome-wide association studies have identified only a few single nucleotide polymorphisms associated with arterial stiffness, the results have been inconsistent between studies and overlap with other clinical conditions is lacking. Our aim was to investigate a potential shared set of risk single nucleotide polymorphisms between relevant cardiometabolic traits and arterial stiffness. Method: The study population consisted of 2853 individuals (mean age 72 years, 40% men) from the population-based Malmö Diet and Cancer study, Sweden. Carotid-femoral pulse wave velocity, a marker of arterial stiffness, was measured with Sphygmocor. Mendelian randomization analyses were performed using the twostage least square regression and multivariate inversevariance weighted methods. Results: There were positive associations between arterial stiffness and genetic risk scores for type 2 diabetes (β=0.03, P=0.04) and fasting plasma glucose (β=0.03, P=0.03), but not for systolic blood pressure, body mass index, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol or triglycerides. Multivariate inversevariance weighted methods confirmed the significant positive association for fasting plasma glucose β coefficients (P=0.006), but not for type 2 diabetes β coefficients (P=0.88). Conclusion: Genetically elevated fasting plasma glucose, but not genetically elevated risk of type 2 diabetes, was associated with arterial stiffness suggesting a causal stiffening effect of glycemia on the arterial wall, independently of type 2 diabetes.
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